Findings of PTSD-specific deficits in default mode network strength following a mild experimental stressor.

Reductions in default mode (DMN) connectivity strength have been reported in posttraumatic stress disorder (PTSD). However, the specificity of DMN connectivity deficits in PTSD compared to major depressive disorder (MDD), and the sensitivity of these alterations to acute stressors are not yet known. 52 participants with a primary diagnosis of PTSD (n = 28) or MDD (n = 24) completed resting-state functional magnetic resonance imaging immediately before and after a mild affective stressor. A 2 × 2 design was conducted to determine the effects of group, stress, and group*stress on DMN connectivity strength. Exploratory analyses were completed to identify the brain region(s) underlying the DMN alterations. There was significant group*stress interaction (p = 0.03), reflecting stress-induced reduction in DMN strength in PTSD (p = 0.02), but not MDD (p = 0.50). Nodal exploration of connectivity strength in the DMN identified regions of the ventromedial prefrontal cortex and the precuneus potentially contributing to DMN connectivity deficits. The findings indicate the possibility of distinct, disease-specific, patterns of connectivity strength reduction in the DMN in PTSD, especially following an experimental stressor. The identified dynamic shift in functional connectivity, which was perhaps induced by the stressor task, underscores the potential utility of the DMN connectivity and raises the question whether these disruptions may be inversely affected by antidepressants known to treat both MDD and PTSD psychopathology.

To study any differences between PTSD and depression in the way the brain talks with itself in its default mode when not doing any particular thing, we did MRI brain scans with 52 people with Depression, but only some had PTSD. We found that mild emotional stress may briefly reduce default mode strength in PTSD, but not in depression. This might help researchers better understand the impact of stress and trauma on the brain.

Neural differentiation of emotional faces as a function of interpersonal violence among adolescent girls.

Interpersonal violence (IV) is associated with altered neural threat processing and risk for psychiatric disorder. Representational similarity analysis (RSA) is a multivariate approach examining the extent to which differences between stimuli correspond to differences in multivoxel activation patterns to these stimuli within each ROI. Using RSA, we examine overlap in neural patterns between threat and neutral faces in youth with IV. Participants were female adolescents aged 11-17 who had a history of IV exposure (n = 77) or no history of IV, psychiatric diagnoses, nor psychiatric medications (n = 37). Participants completed a facial emotion processing task during fMRI. Linear mixed models indicated that increasing hippocampal differentiation of fear and neutral faces was associated with increasing IV severity. Increased neural differentiation of these facial stimuli in the left and right hippocampus was associated with increasing physical abuse severity. Increased differentiation by the dACC correlated with increasing physical assault severity. RSA for most ROIs were not significantly associated with univariate activity, except for a positive association between amygdala RSA and activity to fear faces. Differences in statistically significant ROIs for physical assault and physical abuse may highlight distinct effects of trauma type on encoding of threat vs. neutral faces. Null associations between RSA and univariate activation in most ROIs suggest unique contributions of RSA for understanding IV compared to traditional activation. Implications include understanding mechanisms of risk in IV and trauma-specific treatment selection. Future work should replicate these findings in longitudinal studies and identify sensitive periods for neural alterations in RSA.

Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Biological embedding of early trauma: the role of higher prefrontal synaptic strength.

Background: Early trauma predicts poor psychological and physical health. Glutamatergic synaptic processes offer one avenue for understanding this relationship, given glutamate's abundance and involvement in reward and stress sensitivity, emotion, and learning. Trauma-induced glutamatergic excitotoxicity may alter neuroplasticity and approach/avoidance tendencies, increasing risk for psychiatric disorders. Studies examine upstream or downstream effects instead of glutamatergic synaptic processes in vivo, limiting understanding of how trauma affects the brain.Objective: In a pilot study using a previously published data set, we examine associations between early trauma and a proposed measure of synaptic strength in vivo in one of the largest human samples to undergo Carbon-13 (13C MRS) magnetic resonance spectroscopy. Participants were 18 healthy controls and 16 patients with PTSD (male and female).Method: Energy per cycle (EPC), which represents the ratio of neuronal oxidative energy production to glutamate neurotransmitter cycling, was generated as a putative measure of glutamatergic synaptic strength.Results: Results revealed that early trauma was positively correlated with EPC in individuals with PTSD, but not in healthy controls. Increased synaptic strength was associated with reduced behavioural inhibition, and EPC showed stronger associations between reward responsivity and early trauma for those with higher EPC.Conclusion: In the largest known human sample to undergo 13C MRS, we show that early trauma is positively correlated with EPC, a direct measure of synaptic strength. Our study findings have implications for pharmacological treatments thought to impact synaptic plasticity, such as ketamine and psilocybin.

Abnormalities in the strength of synaptic connections have been implicated in trauma and trauma-related disorders but not directly examined.We used magnetic resonance spectroscopy to investigate the association between early trauma and an in vivo measure of synaptic strength.For people with posttraumatic stress disorder, as early trauma severity increased, synaptic strength increased, highlighting the potential for treatments thought to change synaptic connections in trauma-related disorders.

DSM-5 criterion-a-based trauma types in service members and veterans seeking treatment for posttraumatic stress disorder.

OBJECTIVE: In posttraumatic stress disorder (PTSD), the assumption of the equipotentiality of traumas ignores potentially unique contexts and consequences of different traumas. Accordingly, Stein et al. (2012) developed a reliable typing scheme in which assessors categorized descriptions of traumatic events into six "types": life threat to self (LTS), life threat to other, aftermath of violence (AV), traumatic loss, moral injury by self (MIS), and moral injury by other (MIO). We extended this research by validating the typing scheme using participant endorsements of type, rather than assesor-based types. We examined the concordance of participant and assesor types, frequency, and validity of participant-based trauma types by examining associations with baseline mental and behavioral health problems. METHOD: Interviewers enrolled military personnel and veterans (N = 1,443) in clinical trials of PTSD and helped them select the most currently distressing Criterion-A trauma. Participants and, archivally, assessors typed the distressing aspect(s) of this experience. RESULTS: AV was the most frequently participant-endorsed type, but LTS was the most frequently rated worst part of an event. Although participants endorsed MIS and MIO the least frequently, these were associated with worse mental and behavioral health problems. The agreement between participants and assessors regarding the worst part of the event was poor. CONCLUSION: Because of discrepancies between participant and assessor typologies, clinical researchers should use participants' ratings, and these should trump assessor judgment. Differences in pretreatment behavioral and mental health problems across some participant-endorsed trauma types partially support the validity of the participant ratings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence.

Posttraumatic stress disorder (PTSD) is a devastating condition, for which there are few pharmacological agents, often with a delayed onset of action and poor efficacy. Trauma-focused psychotherapies are further limited by few trained providers and low patient engagement. This frequently results in disease chronicity as well as psychiatric and medical comorbidity, with considerable negative impact on quality of life. As such, off-label interventions are commonly used for PTSD, particularly in chronic refractory cases. Ketamine, an N-methyl-D-aspartate (NDMA) receptor antagonist, has recently been indicated for major depression, exhibiting rapid and robust antidepressant effects. It also shows transdiagnostic potential for an array of psychiatric disorders. Here, we synthesize clinical evidence on ketamine in PTSD, spanning case reports, chart reviews, open-label studies, and randomized trials. Overall, there is high heterogeneity in clinical presentation and pharmacological approach, yet encouraging signals of therapeutic safety, efficacy, and durability. Avenues for future research are discussed.

Psychometric Properties of the Self-Injurious Thoughts and Behaviors Interview-Short Form Among U.S. Active Duty Military Service Members and Veterans.

We assessed the interrater reliability, convergent validity, and discriminant validity of the Self-Injurious Thoughts and Behaviors Interview-Short Form (SITBI-SF) in a sample of 1,944 active duty service members and veterans seeking services for posttraumatic stress disorder (PTSD) and related conditions. The SITBI-SF demonstrated high interrater reliability and good convergent and discriminant validity. The measurement properties of the SITBI-SF were comparable across service members and veterans. Approximately 8% of participants who denied a history of suicidal ideation on the SITBI-SF reported suicidal ideation on a separate self-report questionnaire (i.e., discordant responders). Discordant responders reported significantly higher levels of PTSD symptoms than those who denied suicidal ideation on both response formats. Findings suggest that the SITBI-SF is a reliable and valid interview-based measure of suicide-related thoughts and behaviors for use with military service members and veterans. Suicide risk assessment might be optimized if the SITBI-SF interview is combined with a self-report measure of related constructs.

Proton Magnetic Resonance Spectroscopy in Post-Traumatic Stress Disorder-Updated Systematic Review and Meta-Analysis.

A stressor-related disorder wherein traumatic experience precipitates protracted disruptions to mood and cognition, post-traumatic stress disorder (PTSD) is associated with wide-ranging abnormalities across the body. While various methods have investigated these deviations, only proton magnetic resonance spectroscopy (1H MRS) enables noninvasive measurement of small-molecule metabolites in the living human. 1H MRS has correspondingly been employed to test hypotheses about the composition and function of multiple brain regions putatively involved in PTSD. Here we systematically review methodological considerations and reported findings, both positive and negative, of the current 1H-MRS literature in PTSD (N = 32 studies) to communicate the brain regional metabolite alterations heretofore observed, providing random-effects model meta-analyses for those most extensively studied. Our review suggests significant PTSD-associated decreases in N-acetyl aspartate in bilateral hippocampus and anterior cingulate cortex with less evident effect in other metabolites and regions. Model heterogeneities diverged widely by analysis (I2 < 0.01% to 90.1%) and suggested regional dependence on quantification reference (creatine or otherwise). While observed variabilities in methods and reported findings suggest that 1H-MRS explorations of PTSD could benefit from methodological standardization, informing this standardization by quantitative assessment of the existing literature is currently hampered by its small size and limited scope.

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators.

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; ß*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; ß*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630.

Prefrontal Glutamate Neurotransmission in PTSD: A Novel Approach to Estimate Synaptic Strength in Vivo in Humans.

Background: Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used EPC to investigate the role of prefrontal neurotransmission in trauma-related psychopathology. Methods: Healthy controls (n = 18) and patients with posttraumatic stress (PTSD; n = 16) completed 13C-acetate magnetic resonance spectroscopy (MRS) scans to estimate prefrontal EPC, which is the ratio of neuronal energetic needs per glutamate neurotransmission cycle (VTCA/VCycle). Results: Patients with PTSD were found to have 28% reduction in prefrontal EPC (t = 3.0; df = 32, P = .005). There was no effect of sex on EPC, but age was negatively associated with prefrontal EPC across groups (r = -0.46, n = 34, P = .006). Controlling for age did not affect the study results. Conclusion: The feasibility and utility of estimating prefrontal EPC using 13C-acetate MRS were established. Patients with PTSD were found to have reduced prefrontal glutamatergic synaptic strength. These findings suggest that reduced glutamatergic synaptic strength may contribute to the pathophysiology of PTSD and could be targeted by new treatments.

mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression.

Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we examined the effect of mTORC1 inhibition on ketamine's antisuicidal effects. Twenty patients in a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo prior to IV ketamine (0.5 mg/kg). We found ketamine administration resulted in significant improvements across all measures with the largest effect at 24 h with only the Beck Scale for Suicide remaining significant at the two-week follow-up. There were no significant main effects of pretreatment. While these analyses are pilot in nature and overall severity of SI was relatively low, the antisuicidal findings (no effect of rapamycin) being in contrast to the antidepressant effects (prolonged effect with rapamycin), suggest the rapid-acting antisuicidal and antidepressant effects of ketamine may be mechanistically distinct and the trajectories of response, recovery, and relapse may be independent. These findings provide additional evidence of ketamine's antisuicidal effects and highlight the importance of future studies that continue to examine potential differences in mechanisms and trajectory of outcomes.

Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial.

This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.

Effects of Smoking Status and State on Intrinsic Connectivity.

BACKGROUND: Smoking behavior during the first 24 hours of a quit attempt is a significant predictor of longer-term abstinence, yet little is known about the neurobiology of early tobacco abstinence. Specifically, the effects of acute tobacco deprivation and reinstatement on brain function-particularly at the level of large-scale network dynamics and assessed across the entire brain-remain incompletely understood. To address this gap, this study used a mixed within- and between-subjects design to assess the effects of smoking status (yes/no smoker) and state (deprived vs. satiated) on whole-brain patterns of intrinsic connectivity. METHODS: Participants included 42 tobacco smokers who underwent resting-state functional magnetic resonance imaging following overnight abstinence (deprived state) and following smoking reinstatement (satiated state, randomized order across participants). Sixty healthy control nonsmokers underwent a single resting-state scan using the same acquisition parameters. Functional connectivity data were analyzed using both a canonical network-of-interest approach and a whole-brain, data-driven approach, i.e., intrinsic connectivity distribution. RESULTS: Network-of-interest-based analyses indicated decreased functional connectivity within frontoparietal and salience networks among smokers relative to nonsmokers as well as effects of smoking state on default mode connectivity. In addition, intrinsic connectivity distribution analyses identified novel between-group differences in subcortical-cerebellar and corticocerebellar networks that were largely smoking state dependent. CONCLUSIONS: These data demonstrate the importance of considering smoking state and the utility of using both theory- and data-driven analysis approaches. These data provide much-needed insight into the functional neurobiology of early abstinence, which may be used in the development of novel treatments.

Transcranial direct current stimulation targeting the medial prefrontal cortex modulates functional connectivity and enhances safety learning in obsessive-compulsive disorder: Results from two pilot studies.

BACKGROUND: Exposed-based psychotherapy is a mainstay of treatment for obsessive-compulsive disorder (OCD) and anxious psychopathology. The medial prefrontal cortex (mPFC) and the default mode network (DMN), which is anchored by the mPFC, promote safety learning. Neuromodulation targeting the mPFC might augment therapeutic safety learning and enhance response to exposure-based therapies. METHODS: To characterize the effects of mPFC neuromodulation on functional connectivity, 17 community volunteers completed resting-state functional magnetic resonance imaging scans before and after 20 min of frontopolar anodal multifocal transcranial direct current stimulation (tDCS). To examine the effects of tDCS on therapeutic safety learning, 24 patients with OCD completed a pilot randomized clinical trial; they were randomly assigned (double-blind, 50:50) to receive active or sham frontopolar tDCS before completing an in vivo exposure and response prevention (ERP) challenge. Changes in subjective emotional distress during the ERP challenge were used to index therapeutic safety learning. RESULTS: In community volunteers, frontal pole functional connectivity with the middle and superior frontal gyri increased, while connectivity with the anterior insula and basal ganglia decreased (ps < .001, corrected) after tDCS; functional connectivity between DMN and salience network also decreased after tDCS (ps < .001, corrected). OCD patients who received active tDCS exhibited more rapid therapeutic safety learning (ps < .05) during the ERP challenge than patients who received sham tDCS. CONCLUSIONS: Frontopolar tDCS may modulate mPFC and DMN functional connectivity and can accelerate therapeutic safety learning. Though limited by small samples, these findings motivate further exploration of the effects of frontopolar tDCS on neural and behavioral targets associated with exposure-based psychotherapies.